Diabetic Foot Infections By Scott Bergman, Pharm.D., BCPS-AQ ID; and Punit J. Shah, Pharm.D., BCPS Reviewed by Douglas N. Fish, Pharm.D., FCCP, BCPS-AQ ID; Sonal Taylor, Pharm.D., BCACP; and Mary J. Thoennes, RPh, BCACP, NCPS LEARNING OBJECTIVES 1. Distinguish the factors that increase the risk of diabetic foot infections (DFIs) in a patient. 2. Assess the severity and extent of DFI on the basis of clinical tests and findings. 3. Evaluate a patient’s risk factors for multidrug-resistant organisms when selecting an appropriate empiric antimicrobial therapy for DFIs. 4. Analyze differences between therapeutic agents in pharmacokinetics and efficacy depending on the severity and extent of DFI. 5. Design an appropriate antimicrobial treatment and monitoring plan for a patient with a DFI with or without osteomyelitis. 6. Develop a plan to prevent diabetic foot ulcers in the patient with diabetes. INTRODUCTION ABBREVIATIONS IN THIS CHAPTER According to the CDC, the number of Americans with a diagnosis of DFI Diabetic foot infection diabetes more than tripled between 1980 and 2012 (from 5.5 million DFO Diabetic foot osteomyelitis to 21.3 million) (CDC 2014). This number continues to rise, and with DFU Diabetic foot ulcer it, the number of patients at risk of microvascular and macrovascular HBOT Hyperbaric oxygen therapy complications. Foot problems are common in patients with diabe- MRSA Methicillin-resistant tes. Complications related to foot diseases in patients with diabetes Staphylococcus aureus include Charcot arthropathy, foot ulceration, infection, osteomyelitis, MSSA Methicillin-sensitive Staphylococcus aureus and limb amputation. However, the development of a diabetic foot ulcer (DFU) and subsequent infection is preventable. Pharmacists SSTI Skin and soft tissue infection play a vital role by monitoring, educating, and empowering patients. Table of other common abbreviations. This chapter focuses on the treatment of diabetic foot infections (DFIs), including osteomyelitis, in the primary care setting. Epidemiology and Impact Among patients with diabetes, diseases of the feet are more com- mon in men and in individuals older than 60 years. In their lifetime, about 25% of patients with diabetes will have a significant skin and soft tissue infection (SSTI) because of predisposing vascular insuf- ficiency, neuropathy, and impaired immunity. The most common foot infections are DFIs, and these patients have higher recurrence and hospitalization rates (Lipsky 2012). Diabetic foot infections decrease quality of life and increase morbidity, physical and emotional dis- tress, and health care costs. The number of hospital discharges for patients with diabetes and peripheral arterial disease, ulcer/inflam- mation/infection, and neuropathy doubled from 445,000 in 1988 to 890,000 in 2007 (CDC 2014). ACSAP 2016 Book 3 • Infection Primary Care 7 Diabetic Foot Infections Diabetic foot infections can spread contiguously to deeper muscle, difficulty walking and standing, loss of reflexes, and tissues, including bone. If the infection progresses, it may foot deformities, among other problems. Therefore, regular eventually be necessary to amputate the limb. The mean foot care is essential to prevent foot ulcers and associated hospital charge for one episode of foot or toe osteomyelitis morbidity and mortality in patients with diabetes. A compre- is around $19,000. In addition, in 1988–2009, hospital dis- hensive yearly foot examination is recommended; patients charges for nontraumatic lower-extremity amputation in with a history of ulcers, amputations, foot deformities, periph- patients with diabetes increased by 24% (CDC 2014). eral neuropathy, and peripheral arterial disease should have their feet examined at every visit. PATHOGENESIS Other risk factors for foot ulcers and infection include poor glucose control, which impairs immunologic function, espe- Risk Factors for DFUs and Infection cially action of polymorphonuclear (PMN) leukocytes, humoral Foot ulcers and infection usually occur after trauma. Several immunity, and cell-mediated immunity. In addition, patients factors predispose a patient with diabetes to foot ulcers and with diabetes may have decreased local and systemic inflam- infections. Patients with diabetes often have peripheral sen- matory responses to infection and poor wound healing because sory and motor neuropathy: diabetic neuropathy increases of peripheral arterial disease in the affected limb. Peripheral the risk of foot ulcers by 7-fold (Khanolkar 2008). Patients arterial disease is present in 20%–30% of patients with diabetes with diabetes lose the protective sensations for tempera- and in up to 40% of those with DFI; it is also the most important ture and pain and are often unaware of trauma to their feet. predictor for recovery after DFI (Schaper 2012). A multivariate Furthermore, motor neuropathy leads to wasting away of analysis showed that the risk factors most associated with developing foot infections were wounds that penetrated to the bone (OR 6.7), lasted more than 30 days (OR 4.7), were recurrent (OR 2.4), that had a traumatic etiology (OR 2.4), or that occurred BASELINE KNOWLEDGE STATEMENTS in patients with peripheral vascular disease (OR 1.9) (Lavery Readers of this chapter are presumed to be familiar 2006). Box 1-1 lists the risk factors for DFIs. with the following: • General knowledge of the pathophysiology that Complications leads to diabetic foot ulcers and infection in Breaks in skin expose underlying tissues to colonization by patients with diabetes pathogenic organisms including multidrug-resistant organ- • Spectrum of activity and pharmacokinetics of isms such as methicillin-resistant Staphylococcus aureus antimicrobials (MRSA). The resulting infection may begin superficially, but • Diabetes care standards with a delay in treatment and the impaired body defense mechanisms caused by neutrophil dysfunction and vascular Table of common laboratory reference values. insufficiency, it can spread to the contiguous subcutane- ous tissues and deeper structures (e.g., bone). Diabetic foot ADDITIONAL READINGS osteomyelitis (DFO) is present in up to 20% of mild-moder- ate DFIs and 50%–60% of severely infected wounds. Diabetic The following free resources have additional back- foot osteomyelitis increases the likelihood of surgical inter- ground information on this topic: vention, including amputation. • Infectious Diseases Society of America. Clinical Patients with DFIs may also present with signs of systemic practice guideline for the diagnosis and treatment inflammatory response syndrome, as manifested by at least of diabetic foot infections. Clin Infect Dis 2012;54:132-73. • Liu C, Bayer A, Cosgrove SE, et al. Practice guidelines by the Infectious Diseases Society of Box 1-1. Risk Factors for Diabetic Foot America for the treatment of methicillin-resistant Infections Staphylococcus aureus infections in adults and Presence of peripheral vascular disease in the affected children. Clin Infect Dis 2011;52:1-38. • limb • Stevens DL, Bisno AL, Chambers HF, et al. Practice • Poor glycemic control guidelines for the diagnosis and management of • Loss of protective sensation (i.e., neuropathy) skin and soft tissue infections: 2014 update by the • Traumatic foot wound Infectious Diseases Society of America. Clin Infect • Ulceration > 30 days Dis 2014;59:e10-59. • History of recurrent foot ulcers • American Diabetes Association (ADA). Standards • Previous lower-extremity amputation of Medical Care in Diabetes – 2016. Diabetes Care • Improper footwear 2016;39:S1-S112. • Wounds that penetrated to bone ACSAP 2016 Book 3 • Infection Primary Care 8 Diabetic Foot Infections two of the following: WBC greater than 12 × 103 cells/mm3 or Classification of Infection less than 4 × 103 cells/mm3 or 10% bands or more; respira- There are several published classification schemes and wound scoring systems; however, none is considered to be a tory rate greater than 20 breaths/minute or Paco2 less than 32 mm Hg; temperature greater than 38°C or less than 36°C; and gold standard. Examples of classification schemes are those heart rate greater than 90 beats/minute. from the International Working Group on the Diabetic Foot (IWGDF) and the Infectious Diseases Society of America (IDSA). The IWGDF classifies diabetic foot wounds using the ASSESSMENT acronym PEDIS (perfusion, extent, depth, infection, sensa- Is It Infected? tion). The PEDIS grades for DFI are 1–4, with the lowest grade Not all DFUs are infected. Therefore, DFIs must be diagnosed for no symptoms or signs of infection and the highest grade clinically, rather than only reviewing wound culture results, for presence of local and systemic signs and symptoms of because microorganisms can colonize all wounds. Local infection. The IDSA classifies the infection as uninfected, signs and symptoms of infection include swelling, warmth, mild, moderate, or severe. Grading or classification is tenderness, pain, erythema, and purulent secretions. Patients based on local and systemic manifestations, and extent of with peripheral neuropathy may be unable to describe pain infection. Table 1-1 summarizes the IWGDF and IDSA classi- at the infection site. In addition, patients with limb ischemia fication systems. secondary to peripheral vascular disease may not have ery- thema, warmth, or swelling around the infected ulcer. In these Microbiology patients, it may be appropriate to seek secondary signs of For uninfected wounds, specimen collection for culture is infection, such as abnormal coloration